Affinage

NNT

NAD(P) transhydrogenase, mitochondrial · UniProt Q13423

Length
1086 aa
Mass
113.9 kDa
Annotated
2026-06-10
100 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NNT is an inner mitochondrial membrane, redox-driven proton pump that couples the respiratory proton gradient to transfer of reducing equivalents from NADH to NADP+, maintaining the mitochondrial NADPH pool that feeds the thioredoxin/peroxiredoxin and glutathione antioxidant systems (PMID:24722990, PMID:21602486). Heterologous expression of human NNT in yeast confirmed it functions as a transhydrogenase that partially uncouples respiration, and patient-derived cells from primary adrenal insufficiency show that pathogenic variants abolish NAD(P)+ transhydrogenase activity while leaving mitochondrial bioenergetics intact (PMID:21602486, PMID:38261461). The direction of NNT catalysis is set by cellular redox state and membrane potential: in pancreatic β-cells and in oxidized, low-potential conditions NNT runs in reverse, consuming NADPH to generate NADH (PMID:28580284, PMID:33478087). By controlling NADPH and NAD(H) pools, NNT governs reductive carboxylation and the balance between glutamine and glucose catabolism in the TCA cycle (PMID:23504317). NNT activity is acutely enhanced by IL-1β-triggered, PCAF-mediated acetylation at K1042, which raises NADP+ binding affinity to boost NADPH output, sustaining iron-sulfur cluster maintenance and protecting tumor cells from ferroptosis (PMID:37244254). Through this redox/ROS-buffering function NNT is a central regulator of adrenal steroidogenesis, where both loss and overexpression reduce steroidogenic output (PMID:22634753, PMID:29046340); of pancreatic β-cell glucose-stimulated insulin secretion (PMID:28580284); of macrophage and microglial inflammatory responses (PMID:22593545, PMID:39978699); of skin pigmentation via redox-dependent tyrosinase stability (PMID:34233163); and of cardiomyocyte and endothelial redox homeostasis (PMID:32763515, PMID:41274037). Loss-of-function NNT mutations cause familial glucocorticoid deficiency (PMID:22634753), and a gain-of-function variant causes familial sebaceous hyperplasia by enhancing antioxidant capacity (PMID:40709434). NNT expression is itself regulated transcriptionally by MITF and post-translationally by the deubiquitinase USP47 (PMID:39277608, PMID:37924851).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2011 Medium

    Establishing whether human NNT is itself a redox-driven proton-pumping transhydrogenase required reconstituting the isolated enzyme, which heterologous yeast expression provided along with a screenable activity assay.

    Evidence Heterologous expression of human NNT in S. cerevisiae with transhydrogenase and respiratory assays and a fluorimetric screen

    PMID:21602486

    Open questions at the time
    • No high-resolution experimental structure of human NNT
    • Directionality control in intact mammalian cells not addressed
  2. 2012 High

    Linking NNT to human disease defined its physiological role: loss-of-function mutations cause familial glucocorticoid deficiency through failure of ROS detoxification in steroidogenic adrenal cells.

    Evidence Exome sequencing of FGD patients, adrenocortical cell-line knockdown with redox/ROS assays, and Nnt-deficient mice

    PMID:22634753

    Open questions at the time
    • Molecular link between redox imbalance and the steroidogenic defect not fully resolved
    • Tissue-selectivity of the adrenal phenotype unexplained
  3. 2012 Medium

    Whether NNT shapes innate immunity was tested by manipulating it in macrophages, showing NNT dampens ROS-driven inflammatory signaling and bacterial responses.

    Evidence NNT overexpression in macrophages plus Nnt-null mouse infection model with ROS, MAPK, and cytokine readouts

    PMID:22593545

    Open questions at the time
    • Direct molecular target downstream of redox change not identified
    • Single lab
  4. 2013 High

    How NNT integrates into central carbon metabolism was clarified: by setting NAD(P)H/NAD(P)+ ratios it coordinates reductive carboxylation versus glucose oxidation in the TCA cycle.

    Evidence Stable-isotope flux analysis with NNT loss- and gain-of-function in melanoma and renal carcinoma cells

    PMID:23504317

    Open questions at the time
    • In vivo relevance of the flux shifts not established
    • Does not address directional switching of NNT
  5. 2014 High

    The mechanistic basis for NNT's antioxidant function was tied to respiration-dependent NADPH supply feeding the thioredoxin/peroxiredoxin system for H2O2 removal.

    Evidence Pharmacological inhibition and knockdown in brain mitochondria and dopaminergic cells with H2O2 consumption and Prx redox readouts

    PMID:24722990

    Open questions at the time
    • Relative contribution versus other NADPH sources not quantified here
    • In vivo neuronal consequence not tested
  6. 2017 High

    Resolving NNT's catalytic direction in vivo, β-cell studies showed it runs in reverse at low glucose and that this redox switching shapes glucose-stimulated insulin secretion.

    Evidence NNT-null vs wild-type islets with adenoviral rescue, live glutathione redox probes, and dynamic insulin secretion assays

    PMID:28580284

    Open questions at the time
    • Molecular sensor coupling NNT directionality to glucose not defined
    • Exocytosis amplification mechanism incompletely mapped
  7. 2017 Medium

    NNT's role in cancer cell fitness was probed, linking its control of NAD+/NADPH to HIF-1α stability, HDAC1/p53 acetylation, and proliferation.

    Evidence NNT knockdown in SK-Hep1 cells with flux analysis and multiple pathway readouts

    PMID:28478381

    Open questions at the time
    • Single cell line
    • Causal chain from cofactor change to each downstream node not isolated
  8. 2017 Medium

    Adrenal transcriptomics across three isogenic genotypes established NNT as a dose-sensitive regulator, since both under- and overexpression depress steroidogenesis and antioxidant gene expression.

    Evidence RNA-seq and corticosterone measurement in Nnt-null, wild-type, and overexpressing mice

    PMID:29046340

    Open questions at the time
    • Mechanism of overexpression toxicity not defined
    • Single lab
  9. 2020 High

    NNT was shown to control skin pigmentation through a UVB/MITF-independent redox mechanism that stabilizes tyrosinase and promotes melanosome maturation.

    Evidence Small-molecule NNT inhibition on human skin ex vivo plus mouse and zebrafish models with tyrosinase stability and eumelanin assays

    PMID:34233163

    Open questions at the time
    • Redox species that controls tyrosinase degradation not pinpointed
    • Degradation machinery involved not identified
  10. 2020 Medium

    Endothelial studies extended NNT's antioxidant role to vascular biology, showing its loss elevates mitochondrial ROS and disrupts bioenergetics in response to angiotensin II.

    Evidence NNT shRNA knockdown in human aortic endothelial cells with redox, membrane potential, ATP, and eNOS assays

    PMID:32763515

    Open questions at the time
    • eNOS Ser1177 phosphorylation increase without NO change unexplained
    • Single lab
  11. 2023 High

    A regulatory layer was uncovered: IL-1β-driven PCAF acetylation of NNT at K1042 enhances NADP+ binding and NADPH output, protecting tumor cells from ferroptosis and immune attack.

    Evidence Co-IP/fractionation for PCAF, acetylation site mapping, K1042 mutagenesis, NADP+ binding and ferroptosis assays, PD-1 blockade studies

    PMID:37244254

    Open questions at the time
    • Deacetylase counteracting K1042ac not identified
    • Generality beyond the tumor context tested unclear
  12. 2023 Medium

    NNT protein stability was shown to be set by deubiquitination, identifying USP47 as a regulator upstream of NNT in cutaneous oxidative stress.

    Evidence Usp47-/- mouse skin proteomics plus NNT knockdown in HaCaT cells with mitochondrial ROS and energy assays

    PMID:37924851

    Open questions at the time
    • Direct USP47–NNT interaction and ubiquitin sites not mapped
    • Single lab
  13. 2024 Medium

    Direct enzymatic assays in patient cells established that pathogenic NNT variants abolish transhydrogenase activity without impairing mitochondrial bioenergetics, refining the disease mechanism.

    Evidence Reverse-reaction NNT assay in permeabilized PBMCs from patients, carriers, and controls with oxygen consumption measurements

    PMID:38261461

    Open questions at the time
    • Does not explain tissue specificity of adrenal failure
    • Bioenergetic readout limited to PBMCs
  14. 2025 Medium

    A gain-of-function NNT variant defined the opposite end of the dose-response, causing sebaceous hyperplasia by enhancing antioxidant capacity and ferroptosis resistance.

    Evidence Exome sequencing and functional assays in patient keratinocytes and mutant-NNT sebocytes with NADPH, glutathione, ROS, and ferroptosis readouts

    PMID:40709434

    Open questions at the time
    • Structural basis of the activating effect not resolved
    • Single lab
  15. 2025 Medium

    Longitudinal cardiac and muscle models clarified that NNT protects aging tissue through redox balance rather than core bioenergetics, with effects on hypertrophy, diastolic dysfunction, and muscle performance.

    Evidence Isogenic Nnt-/- vs Nnt+/+ mice across ages with echocardiography, HFpEF modeling, mitochondrial H2O2 and respiration assays, and single-nucleus transcriptomics

    PMID:38795789 PMID:40340422 PMID:41274037

    Open questions at the time
    • Fgf1 as NNT-dependent cardiomyocyte-fibroblast mediator only correlative
    • Genetic-background confounds (C57BL/6J Nnt allele) require care in interpretation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NNT directionality is dynamically sensed and switched within intact mammalian tissues, and what governs its dose-sensitive, context-specific phenotypes, remains incompletely defined.
  • No experimental high-resolution structure of human NNT
  • Deacetylase opposing K1042ac unidentified
  • Mechanistic basis of dose-sensitivity (loss vs overexpression both harmful) unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4 GO:0005215 transporter activity 1 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005739 mitochondrion 4
Pathway
R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-1430728 Metabolism 2 R-HSA-5357801 Programmed Cell Death 2
Partners
PCAFUSP47

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 Loss-of-function mutations in NNT (nicotinamide nucleotide transhydrogenase) cause familial glucocorticoid deficiency; NNT knockdown in a human adrenocortical cell line impaired redox potential and increased reactive oxygen species (ROS) levels, and Nnt-deficient mice showed higher adrenocortical cell apoptosis and impaired glucocorticoid production, establishing NNT's role in ROS detoxification in adrenal steroidogenesis. Targeted exome sequencing of FGD patients; NNT knockdown in human adrenocortical cell line with ROS/redox assays; mouse Nnt loss-of-function model with histology and hormone measurements Nature genetics High 22634753
2013 NNT, as a mitochondrial NADH-to-NADPH reducing-equivalent transfer enzyme, coordinates reductive carboxylation and glucose catabolism in the TCA cycle: NNT knockdown inhibits glutamine contribution to the TCA cycle and reductive carboxylation by IDH1/IDH2, while activating glucose oxidation; NNT overexpression stimulates glutamine oxidation and reductive carboxylation and inhibits glucose catabolism, effects correlated with changes in NAD(P)H/NAD(P)+ ratios. Stable isotope tracer metabolic flux analysis; NNT knockdown and overexpression in SkMel5 melanoma and 786-O renal carcinoma cells; biochemical NADPH/NADP+ measurements The Journal of biological chemistry High 23504317
2014 NNT links mitochondrial respiration to H2O2 detoxification in brain mitochondria via the thioredoxin/peroxiredoxin system: pharmacological inhibition of Nnt in isolated brain mitochondria reduced H2O2 consumption only in the presence of respiration substrates; Nnt inhibition or lentiviral knockdown in N27 dopaminergic cells decreased H2O2 catabolism, reduced NADPH, increased oxidized mitochondrial Prx, and sensitized cells to paraquat-induced death. Pharmacological inhibition of NNT in isolated brain and liver mitochondria; lentiviral Nnt knockdown in N27 dopaminergic cells; H2O2 consumption assays; NADPH/NADP+ measurements; Prx redox state assays; cell viability assays The Journal of biological chemistry High 24722990
2017 In pancreatic β-cells, NNT operates primarily in reverse mode (consuming NADPH to support NADH) at non-stimulating glucose concentrations; glucose stimulation reduces NADPH consumption by NNT reverse mode, accounting for the glucose-induced rise in NADPH/NADP+ and decrease in mitochondrial glutathione oxidation. Loss of NNT in C57BL/6J islets did not alter Ca2+ influx or mitochondrial events but markedly reduced both phases of glucose-stimulated insulin secretion (GSIS) by altering Ca2+-induced exocytosis and its metabolic amplification. Comparison of NNT-null C57BL/6J vs. wild-type C57BL/6N islets; adenoviral NNT re-expression in J-islets; glutaredoxin 1-fused roGFP2 mitochondrial/cytosolic glutathione probes; biochemical NADPH/NADH measurements; dynamic insulin secretion assays; Ca2+ imaging Molecular metabolism High 28580284
2017 NNT is essential for homeostasis of NADH and NADPH pools in cancer cells; NNT knockdown in SK-Hep1 cells decreased NAD+ and NADPH, increased α-ketoglutarate/succinate ratio leading to reduced HIF-1α levels and HIF-1α-regulated gene expression, reduced HDAC1 activity, increased p53 acetylation, increased dependence on oxidative phosphorylation, and impaired proliferation and tumorigenicity. NNT knockdown in SK-Hep1 cells; stable isotope tracer metabolic flux analysis; measurement of HIF-1α, HDAC1 activity, p53 acetylation; proliferation and tumorigenicity assays Redox biology Medium 28478381
2017 Transcriptomic profiling of adrenals from Nnt wild-type (C57BL/6N), Nnt-null (C57BL/6J), and BAC-transgenic Nnt-overexpressing mice showed that both under- and overexpression of NNT reduces adrenal steroidogenic output, correlating with decreased expression of mitochondrial antioxidant enzymes (Prdx3, Txnrd2) and the steroidogenic enzyme Cyp11a1, establishing NNT as a central regulator of adrenal redox homeostasis and steroidogenesis. RNA-seq on adrenals from three isogenic mouse models; corticosterone measurements; pathway enrichment analysis The Journal of endocrinology Medium 29046340
2012 NNT regulates macrophage inflammatory responses: NNT overexpression in a macrophage cell line decreased ROS and nitric oxide upon LPS activation, impaired MAPK signaling pathway activation, reduced proinflammatory cytokine secretion, and impaired clearance of intracellular bacteria; conversely, C57BL/6J mice lacking functional Nnt showed greater macrophage ROS generation and stronger inflammatory response to Streptococcus pneumoniae infection. NNT overexpression in macrophage cell line; ROS and NO measurements; MAPK activation assays; cytokine secretion assays; intracellular bacterial clearance; in vivo infection model with Nnt-null C57BL/6J mice FASEB journal Medium 22593545
2020 NNT controls cellular redox state and skin pigmentation via a UVB- and MITF-independent mechanism: NNT inhibition causes redox changes that increase tyrosinase protein levels (by reducing tyrosinase degradation), promote melanosome maturation, and elevate eumelanin/pigmentation; topical NNT inhibitors darkened human skin ex vivo, and mice with decreased NNT function and zebrafish with genetic NNT modification displayed increased melanocytic pigmentation. Small-molecule NNT inhibitor topical application on human skin; NNT mouse models; CRISPR genetic modification of NNT in zebrafish; tyrosinase stability assays; melanosome maturation analysis; eumelanin quantification Cell High 34233163
2015 Loss-of-function mutations in NNT are associated with left ventricular noncompaction (LVNC); suppression of nnt in zebrafish caused early ventricular malformation and contractility defects likely driven by altered cardiomyocyte proliferation; in vivo complementation with mutant human NNT failed to rescue nnt morpholino-induced heart dysfunction, indicating haploinsufficiency. Whole exome sequencing; zebrafish nnt morpholino knockdown with cardiac phenotyping; in vivo complementation with human NNT constructs Circulation. Cardiovascular genetics Medium 26025024
2020 NNT critically regulates mitochondrial redox balance and endothelial function in response to angiotensin II: NNT knockdown in human aortic endothelial cells elevated mitochondrial ROS, impaired glutathione peroxidase and reductase activities, reduced NADPH/NADP+ ratio, disrupted mitochondrial membrane potential, impaired ATP production, and augmented eNOS phosphorylation at Ser1177 without increasing eNOS activity or NO production. NNT shRNA knockdown in human aortic endothelial cells; mitochondrial ROS measurement; glutathione enzyme activity assays; NADPH/NADP+ ratio; mitochondrial membrane potential; ATP production; eNOS phosphorylation and activity assays Redox biology Medium 32763515
2023 IL-1β stimulation causes acetylation of NNT at lysine K1042 (NNT K1042ac) via PCAF (p300/CBP-associated factor), which translocates to mitochondria upon IL-1β stimulation; K1042 acetylation enhances NNT enzymatic activity by increasing NNT's binding affinity for NADP+, boosting NADPH production, which sustains iron-sulfur cluster maintenance and protects tumor cells from ferroptosis and immune evasion. Co-IP and mitochondrial fractionation for PCAF translocation; acetylation site mapping; NADP+ binding affinity assays; site-directed mutagenesis of K1042; iron-sulfur cluster assays; ferroptosis assays; PD-1 blockade combination studies Molecular cell High 37244254
2016 A 3D structural model of human NNT based on bacterial transhydrogenase crystal structures identified key functional residues including the NAD binding site, the proton canal, and the dimerization interface; the flexible linker between domains II and III and a salt bridge between Arg882 and Asp830 are critical for domain III conformational changes associated with NNT's functional cycle; disease-causing FGD and LVNC missense variants map to these functionally critical regions. Homology modeling using bacterial transhydrogenase experimental structures; sequence-structure analysis; mapping of disease variants onto structural model Human mutation Low 27459240
2021 NNT expression is transcriptionally regulated by MITF (microphthalmia-associated transcription factor) through direct binding to canonical E-BOX sequences proximal to the NNT promoter; MITF-driven NNT expression contributes to a global antioxidant program reducing cytosolic and mitochondrial ROS in melanoma cells. ChIP for MITF binding to NNT promoter E-BOX; ROS measurements in MITF-manipulated melanoma cells; NNT functional assays; zebrafish melanoma model Scientific reports Medium 39277608
2021 In skeletal muscle mitochondria (SMM), NNT supplies NADPH capable of supporting up to 600 pmol/mg/min of H2O2 removal; however, NNT-null (Nnt-/-) SMM maintained H2O2 removal at wild-type levels due to compensatory ~70% elevation in total activities of concurrent NADP+-reducing enzymes (IDH2, malic enzymes, glutamate dehydrogenase). Comparison of SMM from Nnt+/+ and Nnt-/- mice; H2O2 removal assays in intact and detergent-solubilized mitochondria; enzymatic activity assays for IDH2, malic enzymes, glutamate dehydrogenase; oxygen consumption measurements Archives of biochemistry and biophysics Medium 34043997
2021 NNT activity direction is determined by cellular redox state: in cystic fibrosis (CF) cells, NNT protein is elevated ~70% but NNT activity is ~30% lower than wild-type; the oxidized cellular redox state combined with low mitochondrial membrane potential drives NNT to operate in reverse mode (consuming NADPH to produce NADH), reducing its antioxidant function. Spectrophotometric NNT activity assays; western blotting for NNT protein; NADPH and NADH level measurements; mitochondrial ROS quantification; mitochondrial membrane potential measurements in CF vs. wild-type cells International journal of molecular sciences Medium 33478087
2011 Human NNT was functionally expressed in Saccharomyces cerevisiae for the first time; mitochondria isolated from NNT-expressing yeast showed six-fold higher transhydrogenase activity than wild-type yeast mitochondria and partially uncoupled respiration, confirming NNT acts as a redox-driven proton pump; a fluorimetric assay for NNT activity in permeabilized yeast was developed and validated for pharmacological compound screening. Heterologous expression of human NNT cDNA in yeast; transhydrogenase activity assay in isolated yeast mitochondria; respiratory measurements; fluorimetric assay development and pharmacological compound library screen Journal of biomolecular screening Medium 21602486
2022 NNT is silenced by DNA hypermethylation in cisplatin-resistant NSCLC cells; NNT overexpression reduced cisplatin resistance primarily by inhibiting protective autophagy through decreasing NAD+ levels and thereby inactivating SIRT1 (not through direct NADPH/ROS effects); targeted demethylation of the NNT CpG island via CRISPR/dCas9-Tet1 restored NNT expression and reduced autophagy and cisplatin resistance. DNA methylation analysis; NNT overexpression in A549/DDP cells; autophagy assays; NAD+ level measurements; SIRT1 activity assays; NAD+ precursor rescue experiments; CRISPR/dCas9-Tet1 targeted demethylation Archives of toxicology Medium 36336710
2023 USP47 (ubiquitin-specific protease 47) regulates NNT protein stability through direct deubiquitination: proteomic analysis of Usp47-/- mouse skin showed NNT downregulation; NNT knockdown in irradiated HaCaT cells elevated mitochondrial ROS and mitochondrial membrane potential and impaired energy production, establishing NNT as a downstream effector of USP47 in cutaneous oxidative stress responses. Usp47-/- mouse skin models (radiation and imiquimod); proteomic analysis; NNT knockdown in HaCaT cells; mitochondrial ROS assays; mitochondrial membrane potential assays; ATP production measurements Toxicology and applied pharmacology Medium 37924851
2025 PARP14 positively regulates NNT expression in microglia; loss of NNT caused ROS accumulation and microglial inflammation, which was suppressed by NNT overexpression or by the ROS inhibitor N-Acetylcysteine; PARP14-mediated NNT upregulation suppresses microglial activation and alleviates depressive-like behavior in CUS mice. PARP14 knockdown/overexpression in hippocampus of CUS mice; microglial-targeted PARP14 overexpression; NNT overexpression rescue; ROS measurements; NAC treatment; depressive behavioral testing Brain, behavior, and immunity Medium 39978699
2025 NNT promotes diastolic dysfunction in cardiometabolic HFpEF: isogenic Nnt+/+ mice subjected to HFD+L-NAME developed significantly worse diastolic dysfunction (elevated E/e', E/A, diastolic stiffness, myocardial fibrosis) compared to Nnt-/- mice; Nnt+/+ mice showed 40% reduction in NAD+ and 38.8% reduction in GSH:GSSG ratio after HFD+L-NAME; single-nucleus ligand-receptor analysis implicated Fgf1 as a putative NNT-dependent mediator of cardiomyocyte-to-fibroblast signaling in fibrosis. Isogenic Nnt+/+ vs. Nnt-/- mouse model in C57BL/6N background; HFD+L-NAME 2-hit HFpEF model; echocardiography; liquid chromatography-mass spectrometry for NAD+/glutathione; histology for fibrosis; single-nucleus transcriptomics and ligand-receptor analysis Circulation research Medium 40340422
2024 Pathogenic NNT variants in patients with primary adrenal insufficiency result in complete absence of NAD(P)+ transhydrogenase activity (<4% of controls) in peripheral blood mononuclear cells, independent of the specific variant; heterozygous carrier parents have approximately half normal NNT activity; pathogenic NNT variants do not impair mitochondrial bioenergetic function (oxygen consumption) in PBMCs. Reverse reaction NNT enzymatic assay in digitonin-permeabilized PBMCs from patients, carriers, and controls; western blotting for NNT protein; RT-qPCR; mitochondrial oxygen consumption; validated in mouse NNT-null PBMC samples European journal of endocrinology Medium 38261461
2025 A gain-of-function missense variant in NNT (c.2063T>G, p.Leu688Trp) causes premature diffuse familial sebaceous hyperplasia by enhancing NNT antioxidant capacity: patient-derived keratinocytes and NNT-knockdown sebocytes overexpressing mutant NNT showed elevated NADPH/NADP+ ratio, increased glutathione, decreased ROS, and decreased susceptibility to ferroptosis compared to wild-type NNT. Whole-exome sequencing; functional assays in patient-derived keratinocytes; NNT-knockdown SZ95 sebocytes with mutant NNT overexpression; NADPH/NADP+ quantification; glutathione assays; ROS measurements; C11-BODIPY ferroptosis assays; flow cytometry; electron microscopy of mitochondria The British journal of dermatology Medium 40709434
2024 NNT deficiency causes age-dependent skeletal muscle bioenergetic impairment: Nnt-/- mice showed decreased respiratory rates in soleus and vastus lateralis muscles at middle and older ages (but not in young mice), increased centralized nuclei in older soleus fibers, and worsened wire-hang performance; soleus, the muscle with highest NNT expression, was most affected by NNT loss during aging. Nnt-/- vs. Nnt+/+ mice across three ages; wire-hang locomotor performance test; mitochondrial respiration in fiber bundles from multiple muscles; histology with centralized nuclei scoring; NNT expression profiling across muscles Experimental gerontology Medium 38795789
2019 Saturated fatty acid palmitate decreases NNT expression in PBMCs, reducing NADPH and glutathione and increasing ROS and Th17 proinflammatory cytokines; genetic inhibition of NNT recapitulated these effects; obese subjects had lower NNT and glutathione expression compared to lean subjects, identifying NNT as a palmitate-regulated rheostat of redox balance in immune cells. Palmitate treatment of PBMCs from lean subjects; genetic NNT inhibition in PBMCs; NADPH, glutathione, ROS measurements; cytokine assays; comparison with obese vs. lean subjects Biomolecules Medium 30823587
2021 NNT downregulation in clear cell renal cell carcinoma is mediated by HIF2α, which enhances miR-455-5p expression via HIF2α-response elements in the miR-455-5p promoter; miR-455-5p in turn suppresses NNT expression by binding to its 3' UTR. Reduced NNT leads to decreased lipid browning-mediated tumor cell 'slimming', promoting tumor progression. HIF2α knockdown followed by NNT expression analysis; ChIP for HIF2α binding to miR-455-5p promoter; luciferase reporter assay confirming miR-455-5p targeting of NNT 3' UTR; cell line and animal models Clinical and translational medicine Medium 33463050
2025 NNT deficiency in aged mice causes cardiac hypertrophy and moderately reduced ejection fraction/fractional shortening, associated with increased mitochondrial H2O2 release under specific conditions; mitochondrial bioenergetic parameters and Ca2+ retention capacity were largely unaffected by Nnt genotype at all ages, indicating NNT protects aging heart through redox balance maintenance without being essential for bioenergetics. Nnt-/- vs. Nnt+/+ mice assessed at 5, 12, and 23 months; echocardiography; mitochondrial H2O2 production assays; mitochondrial respiration; Ca2+ retention capacity assays; cardiac histology Redox biology Medium 41274037

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency. Nature genetics 180 22634753
2010 Diet-induced obesity in two C57BL/6 substrains with intact or mutant nicotinamide nucleotide transhydrogenase (Nnt) gene. Obesity (Silver Spring, Md.) 148 20057372
2013 Cofactor balance by nicotinamide nucleotide transhydrogenase (NNT) coordinates reductive carboxylation and glucose catabolism in the tricarboxylic acid (TCA) cycle. The Journal of biological chemistry 106 23504317
2023 IL-1β-associated NNT acetylation orchestrates iron-sulfur cluster maintenance and cancer immunotherapy resistance. Molecular cell 103 37244254
2017 Nicotinamide nucleotide transhydrogenase (NNT) deficiency dysregulates mitochondrial retrograde signaling and impedes proliferation. Redox biology 67 28478381
2014 Nicotinamide nucleotide transhydrogenase (Nnt) links the substrate requirement in brain mitochondria for hydrogen peroxide removal to the thioredoxin/peroxiredoxin (Trx/Prx) system. The Journal of biological chemistry 67 24722990
2016 NNT mutations: a cause of primary adrenal insufficiency, oxidative stress and extra-adrenal defects. European journal of endocrinology 61 27129361
2018 Long non-coding RNA NNT-AS1 affects progression of breast cancer through miR-142-3p/ZEB1 axis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 56 29710510
2009 The deletion variant of nicotinamide nucleotide transhydrogenase (Nnt) does not affect insulin secretion or glucose tolerance. Endocrinology 56 19906813
2021 NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism. Cell 55 34233163
2018 LncRNA NNT-AS1 is a major mediator of cisplatin chemoresistance in non-small cell lung cancer through MAPK/Slug pathway. European review for medical and pharmacological sciences 54 30070323
2017 Highly expressed long non-coding RNA NNT-AS1 promotes cell proliferation and invasion through Wnt/β-catenin signaling pathway in cervical cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 54 28628975
2012 Nicotinamide nucleotide transhydrogenase (NNT) acts as a novel modulator of macrophage inflammatory responses. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 54 22593545
2023 LncRNA NNT-AS1/hsa-miR-485-5p/HSP90 axis in-silico and clinical prospect correlated-to histologic grades-based CRC stratification: A step toward ncRNA Precision. Pathology, research and practice 53 37244051
2017 Upregulated NNT-AS1, a long noncoding RNA, contributes to proliferation and migration of colorectal cancer cells in vitro and in vivo. Oncotarget 52 27966450
2015 Loss of Function Mutations in NNT Are Associated With Left Ventricular Noncompaction. Circulation. Cardiovascular genetics 48 26025024
2020 Nicotinamide nucleotide transhydrogenase (NNT) regulates mitochondrial ROS and endothelial dysfunction in response to angiotensin II. Redox biology 46 32763515
2017 NNT is a key regulator of adrenal redox homeostasis and steroidogenesis in male mice. The Journal of endocrinology 46 29046340
2018 LncRNA NNT-AS1 promotes the proliferation, and invasion of lung cancer cells via regulating miR-129-5p expression. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 45 29857296
2018 Long non-coding RNA NNT-AS1 sponges miR-424/E2F1 to promote the tumorigenesis and cell cycle progression of gastric cancer. Journal of cellular and molecular medicine 44 30006956
2017 Long noncoding RNA NNT-AS1 promotes hepatocellular carcinoma progression and metastasis through miR-363/CDK6 axis. Oncotarget 44 29179477
2021 CircRNA circ-NNT mediates myocardial ischemia/reperfusion injury through activating pyroptosis by sponging miR-33a-5p and regulating USP46 expression. Cell death discovery 42 34845193
2017 NNT reverse mode of operation mediates glucose control of mitochondrial NADPH and glutathione redox state in mouse pancreatic β-cells. Molecular metabolism 42 28580284
2021 The relationships between LncRNA NNT-AS1, CRP, PCT and their interactions and the refractory mycoplasma pneumoniae pneumonia in children. Scientific reports 37 33479472
2020 LncRNA NNT-AS1 contributes to the cisplatin resistance of cervical cancer through NNT-AS1/miR-186/HMGB1 axis. Cancer cell international 37 32489326
2020 Mylk3 null C57BL/6N mice develop cardiomyopathy, whereas Nnt null C57BL/6J mice do not. Life science alliance 35 32213617
2021 Serum long non‑coding RNA NNT‑AS1 protected by exosome is a potential biomarker and functions as an oncogene via the miR‑496/RAP2C axis in colorectal cancer. Molecular medicine reports 33 34132374
2020 LncRNA NNT-AS1 promotes non-small cell lung cancer progression through regulating miR-22-3p/YAP1 axis. Thoracic cancer 33 31923353
2020 LncRNA NNT-AS1 promote glioma cell proliferation and metastases through miR-494-3p/PRMT1 axis. Cell cycle (Georgetown, Tex.) 32 32420808
2020 Long non-coding RNA NNT-AS1 regulates proliferation, apoptosis, inflammation and airway remodeling of chronic obstructive pulmonary disease via targeting miR-582-5p/FBXO11 axis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 30 32768929
2018 Upregulation of long non-coding RNA NNT-AS1 promotes osteosarcoma progression by inhibiting the tumor suppressive miR-320a. Cancer biology & therapy 30 30489194
2020 LncRNA NNT-AS1 promotes lung squamous cell carcinoma progression by regulating the miR-22/FOXM1 axis. Cellular & molecular biology letters 27 32514270
2011 Mammalian NADH:ubiquinone oxidoreductase (Complex I) and nicotinamide nucleotide transhydrogenase (Nnt) together regulate the mitochondrial production of H₂O₂--implications for their role in disease, especially cancer. Journal of bioenergetics and biomembranes 27 21882037
2009 Pancreatic islet expression profiling in diabetes-prone C57BLKS/J mice reveals transcriptional differences contributed by DBA loci, including Plagl1 and Nnt. PathoGenetics 27 19161594
2004 Novel neurotrophin-1/B cell-stimulating factor-3 (NNT-1/BSF-3)/cardiotrophin-like cytokine (CLC)--a novel gp130 cytokine with pleiotropic functions. Cytokine & growth factor reviews 27 15450249
2022 CRISPR-based DNA methylation editing of NNT rescues the cisplatin resistance of lung cancer cells by reducing autophagy. Archives of toxicology 26 36336710
2018 Long noncoding RNA NNT-AS1 promotes gastric cancer proliferation and invasion by regulating microRNA-363 expression. Journal of cellular biochemistry 24 30324628
2024 NNT-AS1 in CAFs-derived exosomes promotes progression and glucose metabolism through miR-889-3p/HIF-1α in pancreatic adenocarcinoma. Scientific reports 23 38521881
2022 Widespread discrepancy in Nnt genotypes and genetic backgrounds complicates granzyme A and other knockout mouse studies. eLife 23 35119362
2020 LncRNA NNT-AS1 regulates the progression of lung cancer through the NNT-AS1/miR-3666/E2F2 axis. European review for medical and pharmacological sciences 23 31957837
2020 Long Non-Coding RNA NNT-AS1 Contributes to Cisplatin Resistance via miR-1236-3p/ATG7 Axis in Lung Cancer Cells. OncoTargets and therapy 23 32431515
2019 Saturated Fatty Acid Activates T Cell Inflammation Through a Nicotinamide Nucleotide Transhydrogenase (NNT)-Dependent Mechanism. Biomolecules 23 30823587
2018 Long non-coding RNA NNT-AS1 contributes to cell proliferation, metastasis and apoptosis in human ovarian cancer. Oncology letters 23 29805655
2021 NNT-induced tumor cell "slimming" reverses the pro-carcinogenesis effect of HIF2a in tumors. Clinical and translational medicine 22 33463050
2020 Overexpression of NNT-AS1 Activates TGF-β Signaling to Decrease Tumor CD4 Lymphocyte Infiltration in Hepatocellular Carcinoma. BioMed research international 22 33426064
2018 Detergent Insoluble Proteins and Inclusion Body-Like Structures Immunoreactive for PRKDC/DNA-PK/DNA-PKcs, FTL, NNT, and AIFM1 in the Amygdala of Cognitively Impaired Elderly Persons. Journal of neuropathology and experimental neurology 22 29186589
2015 A novel homozygous insertion and review of published mutations in the NNT gene causing familial glucocorticoid deficiency (FGD). European journal of medical genetics 20 26548497
2020 Long non-coding RNA NNT-AS1 promotes cholangiocarcinoma cells proliferation and epithelial-to-mesenchymal transition through down-regulating miR-203. Aging 19 32019904
2019 Long non-coding RNA NNT-AS1 functions as an oncogenic gene through modulating miR-485/BCL9 in cholangiocarcinoma. Cancer management and research 19 31616187
2014 A phase I study of MEDI4736, NNT-PD-L1 antibody in patients with advanced solid tumors. Translational lung cancer research 19 25806335
2019 NNT-AS1 enhances bladder cancer cell growth by targeting miR-1301-3p/PODXL axis and activating Wnt pathway. Neurourology and urodynamics 18 31782983
2020 Long non‑coding RNA NNT‑AS1 knockdown represses the progression of gastric cancer via modulating the miR‑142‑5p/SOX4/Wnt/β‑catenin signaling pathway. Molecular medicine reports 17 32468065
2020 The Role of Long Non-Coding RNA NNT-AS1 in Neoplastic Disease. Cancers 17 33113895
2025 Mitochondrial NNT Promotes Diastolic Dysfunction in Cardiometabolic HFpEF. Circulation research 16 40340422
2016 Three-Dimensional Model of Human Nicotinamide Nucleotide Transhydrogenase (NNT) and Sequence-Structure Analysis of its Disease-Causing Variations. Human mutation 16 27459240
2014 NNT pseudoexon activation as a novel mechanism for disease in two siblings with familial glucocorticoid deficiency. The Journal of clinical endocrinology and metabolism 15 25459914
2023 Hypoxia promotes immune escape of pancreatic cancer cells by lncRNA NNT-AS1/METTL3-HuR-mediated ITGB1 m6A modification. Experimental cell research 14 37659467
2021 Loss of Nnt Increases Expression of Oxidative Phosphorylation Complexes in C57BL/6J Hearts. International journal of molecular sciences 13 34198873
2019 Long noncoding RNA NNT-AS1 enhances the malignant phenotype of bladder cancer by acting as a competing endogenous RNA on microRNA-496 thereby increasing HMGB1 expression. Aging 13 31848324
2022 Circ_NNT suppresses the apoptosis and inflammation in glucose-induced human retinal pigment epithelium by regulating miR-320b/TIMP3 axis in diabetic retinopathy. Clinical immunology (Orlando, Fla.) 12 35477026
2021 NADPH supply and the contribution of NAD(P)+ transhydrogenase (NNT) to H2O2 balance in skeletal muscle mitochondria. Archives of biochemistry and biophysics 12 34043997
2021 The long non-coding RNA NNT-AS1 promotes clear cell renal cell carcinoma progression via regulation of the miR-137/ Y-box binding protein 1 axis. Bioengineered 12 34643163
2020 NNT-AS1 modulates prostate cancer cell proliferation, apoptosis and migration through miR-496/DDIT4 axis. Cancer cell international 12 32982585
2019 High expression of long non-coding RNA NNT-AS1 facilitates progression of cholangiocarcinoma through promoting epithelial-mesenchymal transition. American journal of translational research 12 31632521
2024 MITF regulates IDH1, NNT, and a transcriptional program protecting melanoma from reactive oxygen species. Scientific reports 11 39277608
2022 Antisense lncRNA NNT-AS1 promoted esophageal squamous cell carcinoma progression by regulating its sense gene NNT expression. Cell death discovery 11 36270987
2006 The mitochondria and insulin release: Nnt just a passing relationship. Cell metabolism 11 16399499
2003 Expression of novel neurotrophin-1/B-cell stimulating factor-3 (NNT-1/BSF-3) in murine pituitary folliculostellate TtT/GF cells: pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal peptide-induced stimulation of NNT-1/BSF-3 is mediated by protein kinase A, protein kinase C, and extracellular-signal-regulated kinase1/2 pathways. Endocrinology 11 14605001
2021 LncRNA-NNT-AS1 contributes to the progression of glioma by miR-582-5p/EZH2 axis. Cytotechnology 10 34149178
2021 LncRNA NNT-AS1 regulates proliferation, ECM accumulation and inflammation of human mesangial cells induced by high glucose through miR-214-5p/smad4. BMC nephrology 9 34742256
2022 Long-Term Follow-Up of Three Family Members with a Novel NNT Pathogenic Variant Causing Primary Adrenal Insufficiency. Genes 8 35627102
2020 Enhanced expression of nicotinamide nucleotide transhydrogenase (NNT) and its role in a human T cell line continuously exposed to asbestos. Environment international 8 32187573
2020 The energetic cost of NNT-dependent ROS removal. The Journal of biological chemistry 8 33246940
2022 Computational epigenetic landscape analysis reveals association of CACNA1G-AS1, F11-AS1, NNT-AS1, and MSC-AS1 lncRNAs in prostate cancer progression through aberrant methylation. Scientific reports 7 35715447
2021 Cellular Redox State Acts as Switch to Determine the Direction of NNT-Catalyzed Reaction in Cystic Fibrosis Cells. International journal of molecular sciences 7 33478087
2020 Nicotinamide Nucleotide Transhydrogenase (Nnt) is Related to Obesity in Mice. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 7 32629517
2023 A novel mutation in the NNT gene causing familial glucocorticoid deficiency, with a literature review. Annales d'endocrinologie 6 37352919
2020 Long noncoding RNA NNT-AS1 functions as an oncogene in breast cancer via repressing ZFP36 expression. Journal of biological regulators and homeostatic agents 6 32691576
2024 Aging-dependent mitochondrial bioenergetic impairment in the skeletal muscle of NNT-deficient mice. Experimental gerontology 5 38795789
2022 Long non-coding RNA NNT-AS1 positively regulates NPM1 expression to affect the proliferation of estrogen-mediated endometrial carcinoma by interacting. Journal of Cancer 5 34976175
2025 PARP14 inhibits microglial activation via NNT to alleviate depressive-like behaviors in mice. Brain, behavior, and immunity 4 39978699
2024 Lack of NAD(P)+ transhydrogenase activity in patients with primary adrenal insufficiency due to NNT variants. European journal of endocrinology 4 38261461
2020 NNT in NSCLC: No need to worry? The Journal of experimental medicine 4 32294154
2023 Ubiquitin-specific peptidase 47 (USP47) regulates cutaneous oxidative injury through nicotinamide nucleotide transhydrogenase (NNT). Toxicology and applied pharmacology 3 37924851
2025 ApoM maintains cellular homeostasis between mitophagy and apoptosis by affecting the stability of Nnt mRNA through the Zic3-ApoM-Elavl2-Nnt axis during neural tube closure. Cell death & disease 2 39827160
2025 Gain-of-function variant in NNT causes premature diffuse familial sebaceous hyperplasia. The British journal of dermatology 2 40709434
2024 Influence of Mitochondrial NAD(P) +  Transhydrogenase (NNT) on Hypothalamic Inflammation and Metabolic Dysfunction Induced by a High-Fat Diet in Mice. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 2 39481390
2023 Testicular impairment in Primary Adrenal Insufficiency caused by Nicotinamide Nucleotide Transhydrogenase (NNT) deficiency - a case report: implication of oxidative stress and importance of fertility preservation. Basic and clinical andrology 2 36918776
2025 Familial Glucocorticoid Deficiency Type 4 Caused by a Novel Mutation in the Nicotinamide Nucleotide Transhydrogenase (NNT) Gene: A Clinical Report of Two Siblings. Cureus 1 39917159
2025 NNT-AS1, A Long Non-coding RNA with Therapeutic Promise in Mycoplasma Pneumoniae Pneumonia via the Mir-410-3p/TMEM14A/Wnt/ΒCatenin Signalling Pathway. Iranian journal of biotechnology 1 40463946
2024 Follow up of a rare case of adrenal insufficiency due to NNT mutation. BMJ case reports 1 38367989
2023 MITF regulates IDH1 and NNT and drives a transcriptional program protecting cutaneous melanoma from reactive oxygen species. bioRxiv : the preprint server for biology 1 38014031
1998 Will angiotensin converting enzyme genotype, receptor mutation identification, and other miracles of molecular biology permit reduction of NNT? American journal of hypertension 1 9717855
2026 Functional mechanism and clinical implications of lncRNA NNT-AS1 in delayed fracture healing. Cytotechnology 0 41541237
2026 Expression of long non-coding RNA NNT-AS1 in children with severe pneumonia and its effect on lipopolysaccharide-induced human embryonic lung fibroblast injury. Hereditas 0 42106800
2026 Sevoflurane pre-treatment attenuates myocardial cell ferroptosis caused by hypoxia and reoxygenation via regulating lncRNA NNT-AS1. Toxicology mechanisms and methods 0 42233473
2025 NNT deficiency alters cardiac structure and function without impairing mitochondrial bioenergetics in aged mice. Redox biology 0 41274037
2025 NNT inhibits microglial activation via mitochondrial oxidative stress in spinal cord injury. Neuroscience letters 0 41354204
2015 A Mutagenesis Assay for Reporter Gene Screening Using Partially Degenerate Oligonucleotides of the Tandems NNT and NNC. BioMed research international 0 26167508
2011 A high-throughput assay for modulators of NNT activity in permeabilized yeast cells. Journal of biomolecular screening 0 21602486

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